ELECTRODIAGNOSTICS OF DISEASES

WITH CONCENTRIC VISUAL FIELD DEFECTS

Ph. D. Thesis

Andrea Pálffy M.D.

Department of Ophthalmology

Faculty of Medicine

University of Szeged

Szeged, Hungary

2010

Publications related to the thesis:

I. Janáky M, Pálffy A, Kolozsvári L, Benedek Gy: Unilateral manifestation of melanoma-

associated retinopathy. Archives of Ophthalmology 2002; 120: 866-67.

II. Janáky M, Fülöp Zs, Pálffy A, Benedek K, Benedek Gy.: Non-arteritic ischaemic optic

neuropathy (NAION) in patients under 50 years of age. Acta Ophthalmologica

Scandinavica 2005; 83: 499-503.

III. Janáky M, Fülöp Zs, Pálffy A, Benedek K, Benedek Gy: Electrophysiological findings

in patients with nonarteritic anterior ischemic optic neuropathy. Clinical

Neurophysiology 2006; 117: 1158-66.

IV. Pálffy A, Szilágyi M, Benedek K: Differential diagnosis of concentric visual field

defects using electrophysiological methods. Szemészet 2006; 143: 64-68.

V. Janáky M, Pálffy A, Fülöp ZS, Szabó Á, Gyetvai T, Liszli P: Differential diagnostics of

nonarteritic anterior ischaemic optic neuropathy (NAION). Szemészet 2006; 143: 17-21.

VI. Janáky M, Pálffy A, Deák A, Szilágyi M, Benedek Gy: Multifocal ERG reveals several

patterns of cone degeneration in retinitis pigmentosa with concentric narrowing of the

visual field. Investigative Ophthalmology and Visual Science 2007; 48: 383-89.

VII. Janáky M, Pálffy A, Horváth Gy, Tuboly G, Benedek Gy: Pattern-reversal

electroretinograms and visual evoked potentials in retinitis pigmentosa. Documenta

Ophthalmologica. Advances in ophthalmology 2008; 117: 27-36.

VIII. Pálffy A, Janáky M, Fejes I, Horváth G, Benedek G: Interocular amplitude differences

of multifocal electroretinograms obtained under monocular and binocular stimulation

conditions. Acta Physiologica (Accepted to publication)

Publications not related to the thesis:

IX. Janáky M, Pálffy A, Deák A, Gallyas É, Benedek Gy: Electrophysiological screening

of hereditary diseases in myopic patients. Szemészet 2002; 139: 217-221.

X. Pálffy A, Gyetvai T, Janáky M, Kolozsvári L: Bilateral metastases of breast cancer –

case report Szemészet 2003; 140: 259-62.

XI. Janáky M, Pálffy A, Fülöp Zs, Szabó Á, Gyetvai T, Liszli P: Paraneoplastic syndromes

of the retina. Description of a case of melanoma-associated retinopathy. Szemészet

2003; 140: 37-41.

XII. Janáky M, Pálffy A, Benedek K, Benedek Gy.: New chapter in the study of visual

evoked potentials - clinical application of the multifocal VEP method. Ideggyógyászati

Szemle 2004; 57: 377-83.

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XIII. Janáky M, Pálffy A, Benedek K, Benedek Gy: New chapter in visual evoked potential

studies: Clinical application of the multifocal VEP method. Ideggyógyászati Szemle

2004; 57: 377–83.

XIV. Gyetvai T, Pálffy A, Vízvári E: Postoperative endophthalmitis: a 6 year-review.

Szemészet 2006; 143: 43-45.

XV. Benedek K, Pálffy A, Bencsik K, Fejes I, Rajda C, Tuboly G, Liszli P: Combined use

of pattern electroretinography and pattern visual evoked potentials in

neuroophthalmological practice. Ideggyógyászati Szemle 2008; 61: 33-41.

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Abbreviations

AD autosomal dominant

AION arteritic ischaemic optic neuropathy

ANOVA analysis of variance

AR autosomal recessive

CAR carcinoma-associated retinopathy

CSF cerebrospinal fluid

CV coefficients of variability

DNA deoxyribonucleic acid

DTL Dawson-Trick-Litzkow

ERG electroretinography

FVEP flash visual evoked potential

GABA gamma-aminobutyric acid

IOP intraocular pressure

ISCEV International Society of Clinical Electrophysiology of Vision

MAR melanoma associated retinopathy

mfERG multifocal electroretinography

mfVEP multifocal visual evoked potential

MRI Magnetic Resonance Imaging

NAION nonarteritic anterior ischemic neuropathy

OP oscillatory potential

PERG pattern electroretinography

PVEP pattern visual evoked potential

RCT retino-cortical time

RP retinitis pigmentosa

RPE retinal pigmentepithel

S simplex

SD standard deviation

U Usher syndrome

VA visual acuity

VEP visual evoked potential

VF visual field

XL-R x-linked recessive

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Contents

1. Introduction …………………………………………………….……….……………….6

2. General description of methods ………………………………………………………...7

2.1. Techniques of visual field testing……………………………………….....................7

2.2. Electrophysiological methods ..………………………………………………..….…7

2.2.1. Electroretinography (ERG) …………………………………………………...7

2.2.2. Multifocal electroretinography (mfERG) …………………………………….8

2.2.3. Pattern electroretinography (PERG) ………………………………………….9

2.2.4. Pattern visual evoked potential (PVEP) ……………………………………..10

3. Methods and results ……………………………………………………………………10

3.1. Techniques of visual field testing ………………………………………………..…10

3.2. Electrophysiological methods ……………………………………………………....11

3.2.1. Electroretinography (ERG) ………………………………………………….11

3.2.2. Multifocal electroretinography (mfERG) ……………………………….......13

3.2.3. Pattern electroretinography (PERG) ………………………………………...16

3.2.4. Pattern visual evoked potential (PVEP) ……………………………………..17

4. Clinical studies …………………………………………………………………………18

4.1. Clinical studies I.: Multifocal ERG reveals several patterns of cone degeneration in

retinitis pigmentosa with concentric narrowing of the visual field ……………......18

4.2. Clinical studies II.: Pattern-reversal electroretinograms and visual evoked potentials

in retinitis pigmentosa …………………………………………………………..…22

4.3. Clinical studies III.: Melanoma-associated retinopathy (MAR) syndrome ……….27

4.4. Clinical studies IV.: Diseases with visual field narrowing ………………………..28

4.4.1. Clinical studies IV/A.: Electrophysiological findings in patients with

nonarteritic anterior ischaemic optic neuropathy …………………………....28

4.4.2. Clinical studies IV/B.: Nonarteritic ischaemic optic neuropathy (NAION) in

patients under 50 years of age ………………………………………….……31

4.5. Clinical studies V.: Differential diagnosis of concentric visual field defects using

electrophysiological methods ………………………………………………………36

5. Discussion ………………………………………………………………………….……38

6. Summary ………………………………………………………………………………..44

7. Conclusions ……………………………………………………………………………..44

8. Acknowledgements …………………………………………………………………….45

9. References ………………………………………………………………………………45

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1. Introduction

Interpretation of the visual field (VF) is a key part of ophthalmic and neurological

examinations. A VF defect indicates a defect in the retina or in the visual pathways. The

damage may affect different locations along the visual pathway, from the optic nerve to the

visual centres of the occipital lobes. Beyond characterizing almost all pathological processes

in the region, VF defects also help to locate the site of the lesion, as lesions interrupting the

function of particular parts of the visual pathway cause specific defects. Thus, perimetric

examination may indicate the site and extent of damage to the visual pathway.

The extent of the involvement of the visual pathway may change during the progression

of the pathological process. In cases with concentric VF narrowing and generalised

sensitivity disturbances the VF defect can be described according to alterations by retinal

quadrants. The depression may be equal or unequal by meridians.

Progression may lead to tunnel vision, by which means a field narrowing yielding 20º

or less residual area on one or both sides is meant. Depending on in which quadrant the larger

isopter constriction is found and in which stage of the disease the characteristic field defect

turns into no longer specific VF constriction, a problem of differential diagnostics also arises.

Retinitis pigmentosa (RP) is a disease with a characteristic tubular field defect,

although it occurs only at the end stage of the disease. The appearance of tunnel vision is not

a pathognomonic sign of RP, since it can develop in other ophthalmological, optic nerve and

intracranial diseases, e.g. in toxic and ischaemic optic neuropathies, paraneoplastic

syndromes, , and retrobulbar processes (like intraorbital infiltration of tumors, endocrine

orbitopathy, etc.) as well. It occurs also in neurological, neuroophthalmological diseases, for

example in diseases with generalized intracranial pressure elevation, direct compression of

the visual pathway, or inflammatory processes and vascular disturbances.

Non-organic causes of VF defects occur in psychiatric diseases (e.g. hysteric

amblyopia), or in case of malingering (visually handicapped benefits, court cases).

For objective detection of the functional alterations in the visual pathway numerous

electrophysiological methods have been developed in the past two decades. These include the

standard electroretinography (ERG), multifocal electroretinography (mfERG), pattern

electroretinography (PERG), visual evoked potential (VEP) and the multifocal visual evoked

potential (mfVEP). The importance of these methods is that the retinal function can be tested

in detail, and minimal cooperation of the patient is sufficient to obtain objective data on the

function of the retina, the visual pathway and the visual cortex.

The aim of our study was to assess the value of the electrophysiological methods in the

differential diagnosis and in the localisation of the defect in diseases with VF alterations. We

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sought to determine which electrophysiological method(s) can help the detection of the cause

of non-characteristic VF defects, and which combination of methods yields the best

localisation of the lesion.

2. General description of methods

2.1. Techniques of visual field testing

There are many methods to evaluate the function of the visual pathways (confrontation

testing, Amsler test, kinetic and static perimetry). The most widely used ones are the kinetic

perimetry (Goldmann perimetry) and the automatic, static method (Humphrey-test, Octopus

perimetry). The selection of the appropriate technique is based on the patient’s history, on the

clinical symptoms (central or peripheral visual disturbances), on the VA, on the

ophthalmoscopic findings (protrusion of the disc: papilloedema, paled optic nerve head or

excavation of the optic nerve head) and on the aetiology of the particular disease. VF

examinations, regardless of which method is used, should never be interpreted without

considering other clinical data, such as the patient’s age, mental and ophthalmological status.

One also has to keep in mind that all of these tests are subjective.

In kinetic perimetry, spots of equal retinal sensitivity in the VF are searched for. By

connecting these areas of equal sensitivity, an isopter is defined. A stimulus of constant size

and intensity is used, which is moved from blind to detectable areas of the VF along a

meridian. The luminance and the size of the target can be changed to plot different isopters.

The larger the size and higher the intensity of the target, the wider the isopter is. This method

is the one most widely used in detecting VF narrowing. The method is both patient-friendly

and time-effective.

In static perimetry we use stationary targets of constant size, but variable intensity.

With this type of perimetry we measure differential light sensitivity for a stimulus presented

against a constant background illumination. The threshold of this differential light sensitivity

represents the brightness of the stimulus that is actually perceived. Thus, this method

indicates retinal light sensitivity at predetermined locations in the VF.

2.2. Electrophysiological methods

2.2.1. Electroretinography (ERG)

Full-field electroretinography is a well-established non-invasive technique that reveals

the electrical activity generated within the retina in response to light stimulation. Different

conditions of retinal adaptation and stimulus intensity make the assessment of global function

of rod and cone pathways and the functional segregation of different retinal layers possible.

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The ERG components are influenced by numerous external and internal factors, such as dark

adaptation of the retina, stimulus intensity, stimulus wavelength, frequency of stimulation,

stimulus duration, size of illuminated retinal area, clarity of media, retinal development, pupil

size, age, sex, refractive errors, circulation of blood, drugs, anaesthesia, and so on.

Considering these factors, the International Society of Clinical Electrophysiology of

Vision (ISCEV) has determined the standard clinical protocols to facilitate inter-laboratory

comparison. An ISCEV standard ERG includes the following responses, named according to

retinal adaptation level and the intensity of the stimulus (flash strength in cd·s·m-2): (1) Dark-

adapted 0.01 ERG (formerly ‘rod response’) consisting of a negative ‘a’ wave representing

the rod function and a positive ‘b’ wave generated mainly by the bipolar cells. ,, (2) Dark-

adapted 3.0 ERG (formerly ‘maximal or standard combined rod–cone response’). It is a

mixed rod-cone response dominated by rod system function. The negative ‘a‘ wave arises in

relation to photoreceptor hyperpolarisation.,,, The large ‘b’ wave reflects

postphototransduction or postreceptoral function.,,,,,,,, (3) Dark-adapted 3.0 oscillatory

potentials (OP) (formerly ‘oscillatory potentials’) consist of small wavelets from the

ascending limb of the ‘b’ wave of maximal ERG, and they are at least partially generated by

the amacrine cells. (4) Light-adapted 3.0 ERG (formerly ‘single-flash cone response’) reflects

activity of the cone system. Its ‘a’ wave is generated by the cone receptors and the ‘b’ wave

comes from the hyperpolarizing ON and OFF bipolar cells. (5) Light-adapted 3.0 flicker ERG

(formerly ‘30 Hz flicker’) arises from the L and M cone pathways, because the S cone

system is relatively insensitive to high temporal frequencies.

2.2.2. Multifocal electroretinography (mfERG)

Multifocal electroretinography (mfERG) provides topographic measure of the

electrophysiological activity of the central retina. Using this technique, multiple local cone-

driven responses are recorded from the retina under light-adapted conditions.

The pattern of the stimulus contains an array of hexagons (61 or 103), that increase in

size with distance from the centre. The sizes of the hexagons are scaled inversely to the

gradient of cone receptor density, so as to produce focal responses of approximately equal

amplitude in control subjects. The radius of the central hexagon is 2°. The retinal size of the

display subtends 30º in radius, similar to the area tested by standard clinical VFs with

automated perimetry. During stimulation, each element is either black or white. The stimulus

contrast is 93%. During stimulation, the display appears to flicker because each hexagon

goes through a pseudo-random sequence (the m-sequence) of black and white presentations.

Each hexagon has a 50% chance of being white or black upon each frame change. Every

hexagon in the array is driven by the same m-sequence of white and black presentations.

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The typical waveform of the basic mfERG response (also called the first-order response

or first-order kernel) is a biphasic wave with an initial negative deflection followed by a

positive peak. There is usually a second negative deflection after the positive peak. These

three peaks are called N1, P1 and N2, respectively.

There is evidence that N1 includes contributions from the same cells that contribute to

the a-wave of the full-field cone ERG, and that P1 includes contributions from the cells

contributing to the cone b-wave and OPs. Although there is some homology between the

mfERG waveform and the conventional ERG, the stimulation rates are higher for the

mfERG, and mfERG responses are mathematical abstractions. Thus, mfERG responses are

not technically ‘little ERG responses’.

2.2.3. Pattern electroretinography (PERG)

Pattern electroretinogram (PERG) is a retinal response evoked by viewing a temporally

alternating black and white checkerboard pattern.

The waveform of the PERG depends on the temporal frequency of the stimulus. At high

temporal frequencies, i.e. above 10 reversals/s (5 Hz), the successive waveforms overlap and

a ’steady-state’ PERG is evoked. The steady-state PERG waveform is roughly sinusoidal,

and interpretation requires measurement of amplitude and phase shift by Fourier analysis.

At low temporal frequencies (<6 reversals per second (rev/s); equivalent to <3 Hz)

transient PERGs are obtained, which are effectively complete before the next contrast

reversal, thus allowing separation and interpretation of the components; this is the standard

method for clinical practice.

The PERG waveform consists of a small initial negative component (N35), which is

followed by a much larger positive component (P50). This, then, is followed by a larger

negative component (N95).

The exact origins of P50 are yet to be ascertained, but it appears partially to arise in

relation to spiking cell function, and partially from non-spiking cells., P50 is driven by the

macular photoreceptors and has been used to provide an effective assessment of macular

function. There is clinical and experimental evidence to indicate that N95 arises in the retinal

ganglion cells.

2.2.4. Pattern visual evoked potential (PVEP)

VEP is an evoked electrophysiological potential extracted from the

electroencephalographic activity of the occipital cortex and can be recorded at the scalp. It

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provides important diagnostic information regarding the functional integrity of the visual

system.,

VEPs can be evoked by flash (flash VEP, FVEP) or pattern stimulation (pattern VEP,

PVEP). FVEP is not sensitive to VA loss, and its intraindividual variability is high. The

flashing light stimulates both the parvocellular and the magnocellular pathways. Conduction

velocities of these two pathways are different; thus, the responses may have two peaks. This

method is applied only when the patient VA is not enough to fixate on the pattern stimulus,

or patient cooperation is impaired.

In the clinical practice, a black and white checkerboard pattern is used for evoking

PVEP. Field size, pattern size and contrast, retinal area of stimulation, and the rate of pattern

presentation can all be varied.

PVEPs are either transient or steady-state. A transient PVEP is to be observed when a

substantial interval elapses between stimulus presentations, allowing the brain to regain its

resting state. Steady-state PVEPs are produced when the brain does not regain its resting

state between stimulus presentations. The temporal rate at which PVEPs change from

transient to steady-state varies, depending on a variety of factors, but in general the transition

occurs at 6-10 presentation per second.

PVEP reflects activity of the sensory visual pathways from the central part of the retina

to the occipital cortex. The projection of the macula is situated on the mesial surface of the

occipital cortex. The other reason why PVEP reflects the activity of central retina is cortical

magnification., The magnification factor is 5.6 mm/degree at the fovea.

The fovea and the parafovea may be selectively stimulated changing the size of the

squares. 10-15 min sized squares stimulate the fovea, while the larger, 50 min squares

stimulate the parafovea.

3. Methods and results

3.1. Techniques of visual field testing

Kinetic VF tests were carried out with a Goldmann perimeter, with a background

intensity of 3.15 apostilbs (asb). A III.e white target was moved from blind to detectable

areas of the VF along a set meridian. The procedure was repeated with the use of the same

stimulus along other meridians, usually spaced every 15°.

Static perimetry was carried out with an OCTOPUS perimeter 1-2-3 (Interzeag AG,

Schlieren, Switzerland). The differential light sensitivity to a stimulus against a constant

background illumination was measured.

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3.2. Electrophysiological methods

Electroretinograms (ERGs), multifocal electroretinograms (mfERGs), pattern

electroretinograms (PERGs) and visual evoked potentials (VEPs) were recorded with the

RETI-Port 32 system (Roland Consult Gmbh, Wiesbaden, Germany). All of the procedures

were performed in accordance with ISCEV standards.

Before the tests, the procedures were fully explained to the patients and their informed

consent was obtained. The research followed the tenets of the Declaration of Helsinki.

In introducing these new methods into the routine clinical practice we determined first

the parameters of the normal values and their variability.

Normal volunteers were free from ophthalmological and systemic diseases. Their VA

was 1.0 on both eyes and the error of refraction was under +1.0 and -3.0 D. Before the tests,

the appropriate refraction was determined and the vision was corrected for the testing

distance.

Data were analyzed with SPSS 13 software (SPSS Inc., Chicago, USA). The normal

data are presented mean, median, standard deviation (SD), percentiles 0.5 and 0.95, and

coefficients of variability (CV).

Our data served as bases of evaluation of the retinal function. The results are

comparable to the national and international results. The variability of our data is not larger

than those of other laboratories.

3.2.1. Electroretinography (ERG)

Standard ERGs were studied in 31 volunteers with good vision. Mean age of the

subjects was 37.2 ± 16.7 years (9-77 years).

The pupils of the volunteers were fully dilated with a combination of Mydrum (Chevin,

Ankefarm) and Neosynephrin (10%, Ursaform) solutions before ERG testing.

Dawson-Trick-Litzkow (DTL) electrodes were routinely used as active electrodes.

Gold cup electrodes, 5 mm in diameter, were used as reference electrodes applied 1 cm

laterally from the ipsilateral orbital rim, and as a ground electrode, placed over the midline of

the forehead (Fz). Sampling rate was 1000 Hz. Impedance was kept below 5 kΩ. Binocular

stimulation was used.

ERGs were recorded by Ganzfeld (full-field) stimulator of RETI-Port 32. (1) Dark-

adapted 0.01 ERG (rod response) was measured after a 20 minutes’ dark adaptation. The

stimulus was a dim white flash of 0.01 cd·s·m-2; with a minimum interval of 2 s between

flashes. (2) Dark-adapted 3.0 ERG (maximal response) was elicited by a white 3.0 cd·s·m-2

flash in the dark-adapted eye. There was an interval of at least 10 s between stimuli. (3)

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Dark-adapted OPs were obtained from the dark-adapted eye, using the 3.0 cd·s·m-2 flash

stimulus. (4) The eye was then restored to photopic conditions (rod-suppressing background

illumination of 17-34 cd/m2) and photopic responses were recorded. Light-adapted 3.0 ERG

(single-flash cone response) was evoked by a 3.0 cd·s·m-2 stimulus, with at least 0.5 s

between flashes. (5) Light-adapted 3.0 flicker ERG (30 Hz flicker) was obtained with 3.0

cd·s·m-2 stimuli. Flashes were presented at a rate of approximately 30 stimuli per second (30

Hz).

The representative ERG curves are presented in Figure 1.

Figure 1. Electroretinograms

of normal patients. ERGs are

presented as continuous lines.

Abscissa: time in ms,

ordinate: amplitude in μV.

Calibration: 6.2 μV, 25 ms.

The amplitudes and latencies were measured for the interpretation of the ERGs. The a-

wave amplitude was measured from baseline to a-wave trough; the b-wave amplitude was

measured from a-wave trough to b-wave peak; the a-wave and b-wave latencies were

measured from the time of the flash to the peak of the wave.

The normal parameters of the waves are presented in Table 1.

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Rod response Mean Median SD Percentile 05 Percentile 95 CV

a latency (ms) 35,13 38,00 6,15 21,25 42,35 0,18b latency (ms) 77,38 79,00 8,32 58,40 88,70 0,11a amplitude (μV) 22,93 14,30 36,06 1,71 101,97 1,57b amplitude (μV) 250,44 238,50 76,07 155,30 399,65 0,30

Maximal response

a latency (ms) 20,06 18,00 4,51 17,00 35,25 0,22b latency (ms) 49,24 49,00 8,77 37,00 73,00 0,18

a amplitude (μV) 210,96 217,50 74,54 17,28 327,25 0,35

b amplitude (μV) 359,79 356,00 90,18 199,25 512,00 0,25

Oscillatory potential

N1 latency (ms) 15,08 15,00 1,47 12,35 18,30 0,10P1 latency (ms) 19,94 20,00 1,30 18,00 22,30 0,07N2 latency (ms) 22,38 22,00 1,04 21,00 25,00 0,05P2 latency (ms) 25,74 26,00 1,62 23,50 29,00 0,06N3 latency (ms) 30,76 30,00 1,23 29,00 34,00 0,04P3 latency (ms) 33,74 34,00 1,90 31,00 37,00 0,06N4 latency (ms) 40,56 40,00 2,18 36,65 44,00 0,05P4 latency (ms) 44,59 45,00 3,55 36,75 51,00 0,08OS1 amplitude (μV) 44,63 44,80 14,64 21,23 72,25 0,33OS2 amplitude (μV) 80,85 84,70 29,99 30,38 136,75 0,37OS3 amplitude (μV) 19,41 16,70 12,27 2,77 43,25 0,63OS4 amplitude (μV) 9,27 7,81 6,10 2,28 23,14 0,66Single-flash cone response

a latency (ms) 16,41 16,00 3,26 12,00 22,75 0,20b latency (ms) 35,32 35,50 2,36 30,75 40,25 0,07a amplitude (μV) 33,92 32,40 11,69 15,60 56,75 0,34b amplitude (μV) 92,65 87,70 33,07 42,55 151,50 0,36

Flicker 30 Hz ERG

N1 latency (ms) 15,24 14,00 3,51 11,40 23,40 0,23P1 latency (ms) 29,79 30,00 1,65 27,00 32,30 0,06flicker N1-P1 latency (ms) 86,53 80,90 28,54 35,16 151,60 0,33

30 Hz amplitude (μV) 33,55 32,00 10,99 20,70 56,70 0,33

Table 1. Normative ERG data in the group of healthy subjects with good vision. (SD:

standard deviation, CV: coefficients of variability)

3.2.2. Multifocal electroretinography (mfERG)

21 volunteers with good vision were involved in this examination. Their ages ranged

from 9 to 72 year with a mean of 33.24 ± 14.9 years. We also analyzed mfERG results

obtained in 35 healthy volunteers with good vision. These provided no evidence for the

advantage of either binocular or monocular stimulating conditions in obtaining mfERGs.

Volunteers’ pupils were fully dilated with a combination of Mydrum (Chevin,

Ankefarm) and Neosynephrin (10%, Ursaform) solutions before testing.

DTL electrodes were used as active recording electrodes. Gold cup electrodes, 5 mm in

diameter, were used as reference electrodes applied 1 cm laterally from the ipsilateral orbital

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rim and as ground electrode placed over the midline of the forehead (Fz). Sampling rate was

1000 Hz. Impedance was kept below 5 kΩ.

The screen–patient distance was 28 cm. Subjects had normal or corrected-to-normal

VA (1.0). Binocular stimulation was used, but when we found the area of best responsiveness

in an eccentric position, we retested the patient with monocular stimulation and compared the

two recordings.

The subject fixated a small central sign in the display containing 61 hexagons. The

radius of the central hexagon was 2°. The retinal size of the display subtended 30º, similar to

the area tested by standard clinical VFs with automated perimetry.

During stimulation, each element was either black or white (93% contrast). The mean

luminance was 51.8 cd/m2, whereas the frame rate was 75 Hz. For a 50.000 times’

amplification, the filters were set between 5 and 100 Hz. Typically the recording took about

7 min.

The mfERG responses had three peaks, N1, P1 and N2, respectively. The N1 response

amplitude was measured from the starting baseline to the base of the N1 trough; the P1

response amplitude was measured from the N1 trough to the P1 peak. The peak times

(implicit times) of N1 and P1 were measured from the stimulus onset.

Figure 2 shows a single mfERG response.

Figure 2. A schematic single mfERG

response to illustrate the major features

of the waveform.

The results were displayed as trace arrays, group averages, quadrants and topographic

(3D) response density plots (Figure 3). Trace arrays can produce an array of the mfERG

traces. This display of the results is useful for visualizing areas of abnormality.

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Figure 3. Sample of mfERG trace arrays (field view) with 61 elements (top left), group

averages (top right), quadrants (bottom left), topographic (3-D) response density plots

associated with trace arrays (bottom right).

For the normative values of mfERGs see Table 2.

Mean Median SD Percentiles 05 Percentiles 95 CVCentrum 127,54 125,00 25,93 96,06 211,00 0,20Ring 2 64,56 66,00 10,03 47,50 80,90 0,16Ring 3 41,98 41,00 6,16 31,30 51,90 0,15Ring 4 29,65 30,00 4,68 20,50 37,90 0,16Ring 5 25,68 24,00 5,72 17,20 35,00 0,22Quadrant 1 34,31 33,50 6,26 26,53 45,90 0,18Quadrant 2 30,68 30,00 4,91 23,04 40,85 0,16Quadrant 3 31,28 30,00 5,24 24,00 41,90 0,17Quadrant 4 31,60 29,00 6,69 22,04 43,00 0,21

Table 2. Normative mfERG data in the group of healthy subjects with good vision.

(SD: standard deviation, CV: coefficients of variability)

3.2.3. Pattern electroretinography (PERG)

PERGs were studied in 68 controls, healthy subjects with good vision. Their mean age

was 34.88 ± 14.77 years, with a range of 10-72 years.

The pupils of the volunteers were not dilated before examinations.

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DTL electrodes were routinely used as active electrodes. Gold cup electrodes 5 mm in

diameter were used as reference electrodes pasted 1 cm laterally from the ipsilateral orbital

rim, and as ground electrodes, placed over the midline of the forehead (Fz). Sampling rate

was 1000 Hz. Impedance was kept below 5 kΩ.

The viewing distance was 33 cm. Subjects had normal or corrected-to-normal VA (1.0).

Binocular stimulation was applied.

Black and white checkerboard patterns with check sizes of 30’ of visual angle served as

the stimulus. The VF extent of the stimulus display was 12º vertically and 16º horizontally.

The contrast of the patterns was 97%. The reversal rate was 2 Hz. Filters were set to 1 and

100 Hz. Two hundred responses were averaged. To test trial to trial variability all tests were

repeated in the same session after a break of 2 min.

The PERG waveform consists of a small initial negative component with a peak time of

approximately 35 ms, N35, which is followed at 45–60 ms by a much larger positive

component (P50). This positive component is followed by a larger negative component at

90–100 ms (N95).

For a representative PERG recording see Figure 4 below.

Figure 4. A normal PERG recording.

Abscissa: time in ms, ordinate: amplitude

in μV. Calibration: 6.2μV, 25 ms

The implicit time of the peaks and the amplitude values of the N35/P50 and P50/N95

were determined. The implicit time was measured from the onset of the contrast reversal to

the peak of the component. The P50 amplitude of the PERG was measured from the trough

of N35 to the peak of P50. In some patients the N35 was poorly defined; in these cases N35

was replaced by the average baseline between time zero and the onset of P50. The N95

amplitude was measured from the peak of P50 to the trough of N95.

Normative PERG data are shown in Table 3.

16

Mean Median SD Percentile 05 Percentile 95 CV

N35 latency (ms) 30,34 30 1,37 28,3 33 0,05

P50 latency (ms) 52,28 52 1,77 50 56 0,03

N95 latency (ms) 93,69 94 5,53 83,3 101 0,06N35-P50 amplitude

(μV) 7,94 7,98 1,97 4,78 11,11 0,25P50-N95 amplitude

(μV) 10,56 10,6 2,38 5,91 14,44 0,23

RCT2 21,03 20,5 4,37 11,65 31,35 0,21

RCT3 50,52 51 4,45 40,2 57,4 0,09

Table 3. Normative data to PERG. (SD: standard deviation, CV: coefficients of

variability, RCT: retino-cortical time, RCT2 is the difference of the VEP N75 amplitude and

the PERG P50 amplitude, RCT3 is the difference of the PVEP P100 amplitude and PERG

P50 amplitude)

3.2.4. Pattern visual evoked potential (PVEP)

To determine of normal values of VEP 50 control subjects were tested. Their mean age

was 38.48 ± 16.14 years, with a range of 7-72 years.

The pupil of the volunteers was not dilated before examinations.

VEPs were recorded through gold cup electrodes. The recording electrode (gold cup)

was placed on the Oz site, the reference electrode on the Fz site. The ground electrode was

placed on the Fpz site. Sampling rate was 1000 Hz. Impedance was kept below 5 kΩ.

The viewing distance of the black-and-white checkerboard stimulus pattern was 33 cm.

Subjects had normal or corrected-to-normal VA (1.0). Monocular stimulation was applied.

The VF extent of the stimulus display was 12º vertically and 16º horizontally. The check

sizes were 20 and 40’of visual angle. In cases of simultaneous recording of PVEP and PERG

the check size was 30’. The contrast was 97%. The reversal rate of the stimulus was 0.9 Hz.

Filters were set between 1 and 100 Hz. One hundred responses were averaged. To test trial to

trial variability, all tests were repeated in the same session after a break of 2 min.

For a standard healthy VEP recording see Figure 5 below.

17

Figure 5. A normal VEP recording. VEPs

are presented as continuous lines. Abscissa:

time in ms, ordinate: amplitude in μV.

Calibration: 6.2 μV, 25 ms.

The PVEP waveform consisted of three peaks: the N75, P100 and N135 peaks. For the

characterization of PVEPs the N75, P100 and N135 latencies and the N75/P100 and

P100/N135 amplitudes were used.

The normative data of PVEP are presented in Table 4.

VEP 64’ Mean Median SD Percentile 05 Percentile 95 CV

N75 latency (ms) 70,64 71,00 4,95 61,40 79,00 0,07

P100 latency (ms) 104,41 105,00 5,53 95,30 114,00 0,05

N135 latency (ms) 145,15 146,00 16,30 120,00 177,20 0,11

N75P100 amplitude (μV) 13,37 13,10 4,92 4,32 22,70 0,37

P100N135 amplitude (μV) 13,35 12,10 5,08 6,48 23,33 0,38

N135-N75 latency differences (ms) 74,44 72,00 17,22 48,20 108,10 0,23

VEP 30’

N75 latency (ms) 73,85 74,00 5,39 63,00 83,00 0,07

P100 latency (ms) 104,54 105,00 4,73 96,30 113,00 0,05

N135 latency (ms) 142,54 146,00 12,83 122,00 165,00 0,09

N75P100 amplitude (μV) 13,82 13,80 4,94 5,80 21,17 0,36

P100N135 amplitude (μV) 15,23 14,10 5,63 8,57 29,51 0,37

N135-N75 latency differences (ms) 68,69 68,00 13,96 47,00 91,00 0,20

Table 4. Normative data to PVEP stimulation. (SD: standard deviation, CV:

coefficients of variability)

4. Clinical studies

4.1. Clinical studies I.: Multifocal ERG reveals several patterns of cone

degeneration in retinitis pigmentosa with concentric narrowing of the visual field

MfERGs of 86 eyes of 43 patients with RP were analyzed. The diagnosis was based on

the major clinical symptom - night blindness - and VF narrowing, the ophthalmoscopic

picture and the characteristic ERG alterations. Mean age of the patients was 31.44 years,

within the range of 6-64 years.

Inclusion criteria were as follows: VA at least 0.2 in the worse eye (allowing fixation

on the central cross in the stimulus pattern) and a residual VF of at least 5-10º as detectable

18

by the Goldmann perimetry with the III.4 white stimulus). None of these patients had

recordable ERG by the standard full field method.

The clinical characteristics of the patients are listed in Table 5.

Patients Eyes

n Gender Genotype Age at Testing Visual acuity n Visual Field n

Total 43 Male 14 U 7 Mean 31.44 Mean 0.63 86 5-10º 19

AD 10 Range 6-64 Range 1.0-0.2 10-15º 33

Female 29 AR 12 15-20º 34

S 14

Group I 14 Male 2 U 4 Mean 28.64 Mean 0.86 28 5-10º 1

AD 5 Range 14-55 1,0-0.8 20 10-15º 9

Female 12 AR 3 0.7-0.5 8 15-20º 18

S 2 <0.4 0

Group II 16 Male 7 U 2 Mean 34.37 Mean 0.65 32 5-10º 2

AD 3 Range 11-55 1,0-0.8 13 10-15º 16

Female 9 AR 4 0.7-0.5 12 15-20º 14

S 7 <0.4 7

Group III 13 Male 5 U 1 Mean 31.33 Mean 0.4 26 5-10º 16

AD 2 Range 6-33 1,0-0.8 3 10-15º 8

Female 8 AR 5 0.7-0.5 12 15-20º 2

S 5 <0.4 11n, number of patients or eyes in the corresponding group. U, Usher syndrome; AD, autosomal dominant; AR,

autosomal recessive; S, simplex.

Table 5. Clinical data of the 43 patients.

MfERGs were recorded according to the standard method described in Chapter 3.2.2.

The mfERG alterations were analysed by trace array, ring and quadrant analysis. The

results were compared to control data from 21 normal volunteers. Data were analyzed with a

two-way ANOVA for group and for category. When ANOVA showed significant

differences, post-hoc analysis was performed with the Dunnett test. P < 0.05 was considered

significant.

The three dimensional presentation generally showed a characteristic central peak

surrounded by very small responses in this disease. However, 13 of the 43 patients had not

even a central peak. On the basis of the best response density of the mfERGs, the patients

were divided into three groups.

Patients in Group I (n=14) presented typical mfERGs and typical VF constrictions on

both sides. The area of best responsiveness was found to be the 31st hexagon, producing a

central peak surrounded by low responses depending on the severity of VF constriction.

However, even if the peripheral rings had almost undetectable kernels, one or two ‘good’

19

responses were almost obtainable in the trace arrays (e.g. 10, 11 or 51). Furthermore, in spite

of the characteristic central peak, the mean amplitude values of the 31. kernels were

significantly subnormal as compared to the normal control values (mean: 43,06 nV/deg2,

range: 17,2-82,2 in patients with RP, and 109, 62 nV/deg2, range 51,3-136 in controls) (see

Figure 6). The differences between these two variables were significant (P<0.00001). In both

the control subjects and the patients with RP, the amplitudes of the responses declined

rapidly toward the outer rings.

Figure 6. (top) mfERG recordings of a control, healthy subject and of a RP patient in

group I (bottom). The best response density was found in the central hexagon, presenting as a

central peak surrounded by very low responses in the three-dimensional presentation. Left:

trace arrays (note the differing calibration). In the bottom left corner, kernel 53 (encircled) is

magnified. The density of the response and the latency of its P1 wave are indicated below it.

Middle: two-dimensional presentations; right: three-dimensional presentations with

calibrations.

The severity of the mfERG alterations did not correlate well with the age of the

patients. Some young patients had a low central peak of the mfERG, and there were older

patients with only a mild sensitivity loss. Their mean VA was 0.86, and only three patients

had a VA of 0.5 in the worse eye (Table 5).

In Group II (n= 16) the best response was found in the 31st position of the trace array

on only one side. In the fellow eye, the best response density appeared in an eccentric

position (Figure 7). This alteration could not be a consequence of a fixation problem, as the

fusion phenomenon keeps the eyes motionless during binocular stimulation. No laterality

differences were found in the refraction or in the VA. The ophthalmoscopic picture of the

20

macular area was similar in both eyes without any abnormality such as cystoid macular

oedema or epiretinal membrane. No history of strabismus or other eye disease could be

responsible for these differences. Latent exo- or esotropia was excluded by careful orthoptic

examination.

Figure 7. MfERG recordings of an RP patient in group II. Top: mfERGs of the eye

with eccentric fixation; bottom: mfERGs of the fellow eye with central fixation. Left: trace

arrays; middle: two-dimensional presentations; right: three-dimensional presentations with

calibrations. To the left of each trace array, the kernel encircled is magnified. The response

density of the response and the latency of its P1 wave are indicated below them.

In cases where the area of best responsiveness was found in an eccentric position, we

repeated the stimulation monocularly as well. In both conditions, the best responses were

found outside the central position. In this group, the averaged mean amplitudes of the

responses in the first ring of the mfERGs were lower than in group I, although some eyes had

a very good central peak. Accordingly, we analyzed the mfERG findings of this group in two

subgroups, depending on the site of the best responses. Group II.A comprised the mfERGs of

the eyes with a central response, and group II.B of those of the fellow eyes with an eccentric

best position. The amplitudes of the responses in the first ring of the group II.A eyes (mean,

47.41 nV/deg2) were almost the same as those in group I. The eyes with eccentric best

responses (group II.B) produced lower amplitudes in the first ring (mean, 24.36 nV/deg2). No

significant side differences between the two eyes were found in the amplitudes of the third,

fourth, and fifth rings or in the four quadrants.

The patients in group II had a mean VA of 0.65. Altogether, 25 of the 32 eyes exhibited

VA better than 0.5 (Table 5.).

21

The patients in Group III (n=13) presented no central peak in the mfERG on either side.

These cases were classified in earlier studies as ‘undetectable mfERGs’ or as artefacts.

However, in some parts of the trace array, we found satisfactorily intact responses in all these

patients (Figure 8.). In these plots, the best responses were found at rather variable sites (e.g.,

hexagons 17 and 47). In some cases, there were two or three peaks of low amplitude in the

three-dimensional presentation of scalar products, making them ‘uneven’, ‘patchy’ in

appearance, or ‘unrecordable’. The mean amplitude in the first ring of the mfERGs in this

group was rather low (19.28 nV/deg2). The appearance of some characteristic, though small,

responses convinced us that these mfERG recordings could not be attributed merely to

artefacts or noise. Repeated examinations gave almost corresponding results.

It is noteworthy that these patients also had satisfactory VA (0.9–0.2, mean, 0.4). Three

eyes had a VA of 0.9, and 12 one had 0.5 or better (0.7– 0.5).

We did not find any relationship between our groups on the basis of the mfERG

recordings and the heredity pattern of the patients.

Figure 8. MfERG recordings of the right eye (top) and left eye (bottom) of a patient

with RP in group III. Left: trace arrays; middle: two-dimensional presentations; right: three-

dimensional presentations with calibrations. To the left of each trace array, the kernel

encircled is magnified. The density of the response and the latency of its P1 wave are

indicated below them. Values of the fourth and fifth rings are omitted. These data were not

informative because the amplitudes were very low.

4.2. Clinical studies II: Pattern-reversal electroretinograms and visual evoked

potentials in retinitis pigmentosa

22

To determine PERG and VEP in RP patients 106 eyes of 53 patients with different

inheritance and durations of RP were analyzed. The age-matched normal values were

calculated by taking into account the PERG parameters of 114 eyes of 57 subjects and the

PVEP parameters of 146 eyes of 73 subjects with good vision and without any

ophthalmological or systemic disease. The clinical characteristics of the patients are

summarized in Table 6.

Inheritance Age at the onset of Age at the examination Visual acuity VF defectthe disease (years) (years) (eyes) (eyes)

n n n nGroup I AD 5 0–20 10 Mean 38.76 Mean: 0.71 34 34n = 17 U 3 20–30 3 Range 14–64 1.0–0.8 16 5º–10º 4Male 4 AR 3 30< 4 0.7–0.5 8 10º–15º 6Female 13 S 6 0.4–0.2 10 15º–20º 24

Group II AD 9 0–20 14 Mean 26.75 Mean: 0.85 32 32 n = 16 U 2 20–30 1 Range 12–70 1.0–0.8 8 5º–10º 2Male 4 AR 4 30< 1 0.7–0.5 21 10º–15º 12Female 12 S 1 0.4–0.2 3 15º–20º 18

Group III AD 10 0–20 12 Mean 35.5 Mean: 0.59 40 40 n = 20 U 2 20–30 4 Range 16–52 1.0–0.8 2 5º–10º 16Male 13 AR 6 30< 4 0.7–0.5 26 10º–15º 4Female 7 S 2 0.4–0.2 12 15º–20º 20AD Autosomal dominant; U Usher syndrome; AR Autosomal recessive; S Simplex

Table 6. Clinical characteristics of the patients

To determine PERG alterations, the N35, P50 and N95 peak times and the N35/P50 and

P50/N95 amplitudes were measured. For the characterization of PVEPs the N75, P100 and

N135 implicit times and the N75/P100 and P100/N135 amplitudes were used. The waveform

alterations of PVEP were regarded as having double P100 peaks if two positive waves

appeared in this interval with a negativity of at least 1 μV. The amplitudes between the larger

positive peak and N135 (Pmax/N135) were used to express the magnitude of the deflection,

independently of whether P1 or P2 was the larger. The broadness of the response was

characterized by the latency differences between N135 and N75.

Statistical analysis was performed only on recordable, reproducible responses. Data are

presented as means ± SD. The results were analyzed by a one-way ANOVA. Subsequent

analysis was performed using Newman-Keuls test. A p-value less than 0.05 was considered

significant. Data were analyzed with STATISTICA 7.1. software (Statsoft Inc., Tulsa, OK).

Seventeen of the 53 patients (32%) yielded recordable, reproducible PERGs. Of these

17 patients, 4 yielded reproducible PERGs from only one eye. Both the N35/P50 and

23

P50/N95 amplitudes of the PERGs were significantly smaller than those of the controls

(Table 7.). We failed to record a normal PERG from any of the patients.

All 53 patients yielded PVEPs which fitted the criteria of reproducibility, though

characteristic alterations were detected in some cases. Depending on the type of these

alterations, we divided the patients into three groups (Figure 9.). No statistical correlation

was found between this division and the age or the duration of RP or the extent of the VF

defect in the patients.

The PVEPs in the three groups exhibited certain characteristics as follows.

All the patients in Group I (n = 17; 32%) had PVEPs with a normal shape. These

PVEPs revealed significantly smaller amplitudes in comparison with the age matched control

group. The peak time of the P100 components was slightly delayed in a few cases, but no

longer than 120 ms. The N135 peaks were at times slightly delayed too, but this alteration did

not reach the level of significance (Table 8.). The interindividual variability of the amplitude

of the PVEPs was rather large.

RP patients ControlsRight eye n=15 Left eye n=15 Right eye n=57 Left eye n=57

N35 Mean ± SD 35.00 ± 4.12 35.38 ± 7.65 30.02 ± 1.22 30.16 ± 1.94Range 27.0–43.0 20.0 - 49.0 27.0 - 34.0 22.0 - 35.0

P50 Mean ± SD 60.64 ± 6.55* 60.92 ± 13.08* 51.72 ± 1.72 51.74 ± 1.65Range 50.0 - 71.0 38.0 - 98.0 47.0 - 56.0 49.0 - 56.0

N95 Mean ± SD 103.73 ± 13.35 95.93 ± 12.06 92.86 ± 5.37 92.93 ± 5.18Range 93.0 - 146.0 70.0 - 116.0 81.0 - 107.0 81.0 - 102.0

N35/P50 Mean ± SD 2.16 ± 0.98* 2.25 ± 2.21 9.55 ± 3.82 9.75 ± 4.24Range 1.1 - 4.1 0.7 - 9.7 4.1 - 24.1 4.2 - 29.6

P50/N95 Mean ± SD 3.39 ± 1.89* 2.78 ± 2.31 12.78 ± 4.67 12.96 ± 5.59Range 1.3 - 9.0 1.3 - 10.5 5.7 - 29.4 5.8 - 37.6

* Denotes significant (P\0.05) differences in comparison to controls

Table 7. Implicit time and amplitude values of PERGs in RP patients (left) and those of

healthy controls (right)

There was no direct correlation between the decrease in amplitude and the age of the

patient or the amplitude and the estimated duration of the disease. In this group, subnormal

PERGs were recorded in 14 eyes, while they were extinguished in 20 eyes.

The VF constriction assessed via the Goldmann perimeter varied in severity (5º–20º).

The upper and lower parts of the field in these patients displayed almost the same degree of

constriction. In some cases, a 5º–10º VF crescent was preserved in the temporal lower part of

the far-peripheral field, close to 90º.

In Group II (n = 16; 30%), the PVEPs had a characteristic, bifid pattern and the

recordings demonstrated well-defined, doubled P100 peaks (P1 and P2). The two

24

components of P100 were separated by about 50 ms. In 6 patients P1 was the larger, while in

another 6 cases P2 was the larger, and in 4 cases there was no difference in amplitude

between the two peaks. The double peak, or ‘W’ form, of the P100 peak may lead to

confusion in the interpretation and in the statistical analysis. It appeared inappropriate to

presume that one or the other was ‘the true’ P100. To express the absolute size of the

deflection, not only the N75/P100 amplitude, but also the Pmax/N135 components were

determined. The decrease in amplitude and the lengthening of the implicit time of P1 were

moderate, but both values revealed a significant difference as compared to the controls

(Table 8.). However, the P2 latencies were rather long and the N135 latencies were greatly

delayed. In several cases, the N135 latency was longer then 200 ms. The inter-peak time of

the negative components (N135 and N75) were significantly longer than those in the controls

(Figure 9.). The Pmax/N135 amplitudes were significantly larger than the N75/P100

amplitudes in this group and than the P100/N135 amplitudes in the two other groups of our

patients. This resulted in the characteristic asymmetrical shape of the curves. Furthermore,

the N135/N75 latency differences were significantly larger than those of the controls and

those observed in Group I.

Subnormal PERGs were recorded in 14 eyes, while the PERGs were extinguished in 18

cases. Similarly to Group I, Goldmann perimetry revealed a concentric narrowing of the

field, with preserved central part. Several patients exhibited the substantial narrowing in the

upper hemifield that approached the central 5º but never involved it. In 14 eyes of the 16

patients, 5–15º of the fields was intact; in the remainder (18 eyes), the central 20º of the

visual field was preserved.

All the recordings in Group III (n = 20; 38%), (40 eyes of 20 patients) revealed a

serious impairment, albeit they were reproducible. They had a delayed implicit time, and

most of the recordings had decreased amplitudes. No true doubled peaks with P1 and P2

could be separated, although the waveform was broad and sometimes very flat. Not only the

P100, but also the N75 and N135 latencies were significantly delayed. It is worth noting that

the latency differences between the N135 and N75 peaks were significantly longer than in the

normal controls.

There were no strict correlations between the VA and the PVEP parameters or VF loss,

since some patients in this group exhibited sufficient VA. However, the mean visual acuity in

Group III was only 0.4. Only 4 eyes of 2 patients yielded recordable, reproducible PERGs.

Upon Goldmann perimetry, the field in 20 eyes was constricted up to 15–20º, while in the

rest there was only a field-remnant of 5º to 10º.

The mean amplitudes and their variability in the three groups are presented in Table 8.

25

Group I Group II Group III Control

Right eye Left eye Right eye Left eye Right eye Left eye Right eye Left eye

N75 75.1 ± 6.47 75.8 ± 6.47 73.6 ± 6.37 75.6 ± 8.66 89.0 ± 15.36* 87.1 ± 4.67* 73.3 ± 6.18 74.2 ± 6.09

Range 63.0 - 87.0 57.0 - 88.0 58.0 - 84.0 58.0 - 90.0 66.0 - 118.0 59.0 - 110.0 60.0 - 85.0 60.0 - 84.0

P100 105.2 ± 6.46 108.5 ± 7.71 109.4 ± 7.51* 108.9 ± 7.62* 134.9 ± 15.58* 136.5 ± 15.84* 103.0 ± 5.95 103.6 ± 5.44

Range 95.0 - 117.0 96.0 - 123.0 97.0 - 120.0 93.0 - 120.0 120.0 - 175.0 114.0 - 175.0 90.0 - 114.0 90.0 - 117.0

P2100 – – 158.4 ± 22.05 156.5 ± 24.54 – – – –

Range – – 132.0 - 201.0 122.0 - 200.0 – – – –

N135 147.3 ± 13.62 155.0 ± 18.90 207.4 ± 37.19* 203.0 ± 34.64* 199.9 ± 24.23* 204.6 ± 25.21* 142.1 ± 13.72 141.9 ± 13.49

Range 120.0 - 170.0 123.0 - 180.0 151.0 - 266.0 151.0 - 253.0 162.0 - 236.0 160.0 - 255.0 121.0 - 180.0 120.0 - 174.0

N75/P100 6.4 ± 3.05* 7.5 ± 3.83 8.3 ± 2.47* 7.5 ± 2.94* 5.1 ± 1.81* 4.6 ± 1.43* 14.4 ± 6.63 14.2 ± 6.77

Range 2.1 - 11.9 1.6 - 14.9 3.7 - 11.7 2.5 - 14.1 2.8 - 9.2 1.9 - 7.7 3.1 - 34.5 2.2 - 34.3

P100/N135 6.9 ± 3.03* 8.1 ± 3.61* 11.5 ± 4.01* 11.8 ± 4.54* 5.8 ± 1.89* 5.7 ± 2.45* 15.4 ± 6.45 15.5 ± 6.12

Range 1.7 - 11.9 1.8 - 14.5 5.7 - 19.5 3.8 - 19.5 1.9 - 8.7 1.0 - 10.2 2.8 - 35.7 6.9 - 35.9

N135-N75 72.2 ± 13.46 79.2 ± 19.37 133.6 ± 34.52* 127.5 ± 30.23* 110.9 ± 22.46* 117.5 ± 25.03* 68.9 ± 14.64 67.7 ± 14.81

Range 51.0 - 101.0 52.0 - 123.0 80.0 - 186.0 80.0 - 169.0 75.0 - 152.0 0 41.0 - 113.0 42.0 - 103.0

For Group II P100/N135 denotes Pmax/N135 values

• Denote significant (P\0.05) differences in comparison to controls

Table 8. Amplitude and latency values (mean ± SD) of PVEPs recorded in the three

groups of RP patients and in controls

Figure 9. Electrophysiological recordings in the three groups of RP patients. Top:

PERG curves in the respective groups. The bottom three curves depict three representative

PVEP recordings in each group. PVEPs are presented as continuous lines. Calibration: 6.2

lV, 25 ms.

26

4.3. Clinical studies III.: Melanoma associated retinopathy (MAR) syndrome

Case history and clinical symptoms of a monocular case with MAR syndrome is

presented.

A cutaneous malignant melanoma was removed from the left leg of a 45-year-old

woman in 1992. Because a systematic search revealed no metastasis, no further therapy was

administered.

One evening in January 2000, she suddenly experienced difficulty seeing in dark

conditions through her right eye, which greatly interfered with her stereovision. She also

reported shimmering lights that fluctuated in brightness.

Because an ophthalmological examination demonstrated good VA and no fundus

alterations, the patient’s complaints were judged to be of psychic origin. Four months later, a

metastatic cutaneous melanoma was removed from her left leg. She underwent chemotherapy

and was referred to our electrophysiological laboratory because of her persisting visual

complaints.

She still had a best-corrected VA of 20/20 on both side. Static perimetry (Octopus)

revealed a marked VF constriction and a general depression of light sensitivity in the right

eye. The left eye exhibited no perimetric alterations (Figure 10.).

Figure 10. A, VF of the right eye

(left) and left eye (right) estimated

using Octopus perimetry. The x- and

y-axes represent dimensions of the VF

in degrees. B, Cumulative defect

curves (Bebie curve) from the 59

central points in rank order

cumulative sensitivity distribution.

The single-flash ERG showed a markedly decreased scotopic response in the right eye,

whereas maximal-intensity stimulation elicited a typical ERG that showed no abnormalities,

a selective b-wave depression with a preserved a wave (Figure 11.). Both the scotopic rod-

isolated response and the maximal response in the left eye were in the normal range. The

averaged ERG and OPs were greatly impaired in the right eye but normal in the left eye.

27

Figure 11. Electrophysiological

recordings from the right eye (left) and

left eye (right) of the patient.

A, Scotopic, rod-isolated response.

B, Maximal, dark-adapted response.

C, Electroretinographic (ERG) response

to red flash. D, Averaged ERG response

to 50 blue flashes. E, Averaged OPs to

50 blue flashes. Calibrations: 50 μV; 100

ms.

Serum immunochemistry revealed strong binding to retinal bipolar cells, similar to that

of a known patient with MAR. This result supported the diagnosis of MAR, so our case was

the first monocular case of this disease.

Five control electrophysiological examinations together with perimetry and

ophthalmoscopy showed no changes during the following 15-month observation period.

Unfortunately, the patient developed agranulocytosis in July 2001 and died of pulmonary

metastases and respiratory failure 1 month later. The family did not allow an autopsy.

4.4. Clinical studies IV.: Diseases with visual field narrowing

4.4.1. Clinical studies IV/A.: Electrophysiological findings in patients with

nonarteritic anterior ischaemic optic neuropathy (NAION)

Beside VF testing (Goldmann kinetic perimetry), scotopic, photopic and flicker ERGs,

mfERGs, PERG and VEP were performed for the objective evaluation of the severity of the

functional loss in 8 NAION patients. The methods are described in Chapter 3.

The diagnosis was based on the history and symptoms: a sudden visual loss or VF loss,

optic disk oedema followed by pallor of the disk, a relative afferent pupillary defect,

altitudinal VF defect with narrowing the isopters (in all four retinal quadrants).

Histories, clinical conditions and suspected predisposing factors are listed in Table 9.

An intracranial cause of the visual loss was excluded by careful neurological

examination, intracranial and orbital MRI and CSF analysis. MRI revealed small white

matter lesions in two patients (Cases 1 and 2). However, these could not be linked to the

visual loss. Other pathologies of disk oedema such as vasculitis, syphilis, borelliosis, herpes

28

simplex, etc. were excluded by serological and immunological tests. Colour Doppler

ultrasonography ruled out intracranial circulatory disturbances.

The electrophysiological results are presented in the form of individual recordings in 3

patients in Figure 12.

Patient Sex Age How long ago Optic disk at attack Visual acuity Optic disk at Visual field at Underlying (yrs) 1. Eyea at examination attack examination disease

2. Eyeb (duration) Was attacked Case 1 M 66 12 yrsa 1.0 D disk oedema 1.0 Pale Temporal upper Hypertension constriction (20 yrs)

2 yrsb 2.0 D disk oedema 1.0 Pale Nasal constriction Diabetes + haemorrhage mellitus (2 yrs)

Case 2 M 62 6 yrsa 3.0 D disk oedema 0.95 Pale Nasal lower con- Hypertension striction 8 mtsb 2.0 D disk oedema + 1.0 Pale Nasal lower con- haemorrhage striction

Case 3 F 52 12 yrsa 3.0 D disk oedema 1.0 Milky-white 50–20º constriction Cardiac disease (12 yrs) 6 yrsb 2.0 D disk oedema 0.85 Milky-white Nasal lower con- strictionCase 4 F 59 15 yrsa 1.0 D disk oedema 0.15 Milky-white Nasal lower con- Type 2 diabetes striction mellitus (15yrs) 13 yrsb Blurred margin 0.15 Pale Nasal lower con- striction

Case 5 F 55 11 yrsa Not visible (cataract) 0.04 Milky-white Not detectable Type 2 diabetes mellitus (15yrs)

cataract

7 yrsb Blurred margin 0.1 Pale Concentric narrow- ing to 10ºCase 6 F 36 5 yrsa 1.0 D disk oedema 0.15 Milky-white Concentric narrow- Type 2 diabetes ing to 20º mellitus (12yrs)

4 yrsb; two 1.0 D disk oedema Light perception Milky-white Not detectableattacks in 2 mts

Case 7 M 64 8 daysa 1.0 D 0.01 1.0 D disk edema Not detectable No underlyingdisease

Normalb Normal 1.0 Normal Normal

Case 8 M 68 3 yrsa 2.0 D disk oedema 0.02 Milky-white Concentric narrow- No underlyinging to 10º disease

Normalb Normal 1.0 Sector-type Normal DecolorationAbbreviations. yrs: years, mts: months, M: male, F: female.a The eye that suffered the first attack.b The eye that was afflicted secondarily (or not), together with the time passed since the attack.

Table 9. Clinical data of the 8 patients (Cases 1–8)

VEPs revealed a serious deterioration in most of the patients. This was especially

marked in 3 cases (Cases 4, 5 and 6) where diabetes mellitus was the underlying disease. All

of them had rather poor VA (Figure 12C). Similarly, the VEPs showed a considerable

amplitude reduction and prolonged P100 peak time upon stimulation of the impaired eye in

the two monocular cases (Cases 7 and 8; Figure 12D). A prolonged P100 implicit time was

also the characteristic VEP alteration in the 3 patients with hypertension (Cases 1, 2 and 3;

29

Figure 12B). Interestingly, the VEPs of the non-involved eyes of the two monocular cases

(Figure 12E) had delayed implicit time, too.

Figure 12. VEP (upper curves) and PERG recordings (lower curves; 30 in reversing checkerboards) upon stimulation of the right eye of a healthy, control subject (A), the right eye of Case 3, a patient with a VF defect and preserved VA (1.0) (B) and the right eye of Case 4, a patient with a serious visual loss (0.15) (C). D and E depict the electrophysiological recordings of the right and left eye, respectively, of Case 7, a patient with monocular affliction. The superimposed curves represent the results of subsequent recordings. Note the correlation between the VEP impairment and the deterioration of VA.

Unpaired t tests were carried out for statistical comparison. An age-matched group of 26

healthy individuals with good vision without any ophthalmological and systemic disease

served as normal controls. Statistical comparison of the amplitude and implicit time values of

the VEPs in patients with NAION and of the age matched normal controls revealed a

significant increase in the implicit time of P100 (P<0.001) and a significant reduction in the

amplitudes between N75 and P100 (P=0.0001) and in those between P100 and N135

(P=0.0005).

In contrast with the severe deterioration observed in the VEPs, the PERG recordings did

not show major abnormalities. There were no statistical differences between the implicit time

values of the patients and the controls, whereas some amplitude reduction was observed in

most cases. Accordingly, statistical comparison of the amplitudes of the PERGs in patients and

controls revealed significant differences (N35–P50: P<0.0005; P50–N95: P<0.00003). These

30

values, however, mostly lay in the range for the age matched normal group (Fig. 2). No

selective P50–N95 amplitude reduction was found. The quotient of the P50–N95 amplitudes

over the N35–P50 amplitudes of the patients (1.32±0.32) was not statistically different from

that for the normal individuals (1.29±0.17). It was noteworthy, however, that the patients with

diabetes mellitus and rather poor vision had better PERGs than those with hypertension.

Patients with old age and long duration of hypertension had the most severe PERG alterations.

No side differences were observed in the PERGs of the monocular cases.

In general, the most striking observation was that patients with poor VA did not have

worse PERGs than those with good vision.

MfERGs had no obvious alterations in the patients.

4.4.2. Clinical studies IV/B.: Nonarteritic ischaemic optic neuropathy

(NAION) in patients under 50 years of age

NAION is a rather frequent cause of sudden visual loss in elderly patients. However, we

found three patients with diabetes, who had the first ischemic attack under the age of 50. We

describe their case histories, clinical and electrophysiological findings.

For objective evaluation of the optic nerve function, visual evoked potentials (VEPs)

were recorded (according to the methods described in Chapter 3.2.4.), whenever a recurrent

event of visual loss or progression of visual impairment was reported.

Intracranial pathological alterations were excluded in all cases by careful neurological

examinations, including CSF examination and cranial and orbital MRI testing (1.5 T; General

Electric, Fairfield, CT, USA). Clinical laboratory tests for diseases that could cause optic

neuritis or vasculitis (erythrocyte sedimentation rate, blood cholesterol level, complete blood

count, antinuclear antibody, rheumatoid factor, C-reactive protein, venereal disease research

laboratory test, herpes, toxocara, IgG in CSF) were routinely performed according to the

general condition of the patient. The care of the patients’ diabetes corresponded to international

standards.

Case 1: A 35-year-old woman had suffered from insulin-dependent diabetes mellitus

from the age of 22 years. Four years prior to this study, she noticed that the vision in her right

eye had suddenly become blurred. A visual impairment was detected not only in the right eye,

but also in the left. VA was 0.5 in the right eye and 0.4 in the left eye. The temporal parts of

both optic discs were pale, and the nasal superior quadrant of the right disc was oedematous.

Goldmann perimetry showed non-characteristic alterations consisting of an enlarged blind spot

and a VF defect in the nasal inferior quadrant of the right eye and concentric narrowing of the

isopters in the left eye (Figure 13A, B).

31

The patient’s young age supported the presumptive diagnosis of multiple sclerosis.

However, fat-suppressed, T1 and T2 sequenced brain and orbital MRI, somatosensory evoked

potential and VEP, and CSF immune tests showed normal results. Intracranial circulation

disturbances could be excluded by the normal results of colour Doppler examination of the

internal carotids and the ophthalmic artery. Chemical analysis of the CSF and blood,

serological tests for syphilis, borelliosis, herpes simplex infection and other immune tests

yielded normal results. The presence of any other systemic diseases that might cause vasculitis

was excluded as well. Nonetheless, the subject’s neurologist put her on steroid treatment.

The next attack of visual impairment occurred 2 years later. VA in the patient’s left eye

decreased to 0.15. Repeated MRI examination failed to show any pathological signs. The

patient was treated with steroids again, without any success. VA remained 0.15 in both eyes.

VF defect covered the central part (Figure 13C, D).

One year later, the subject suddenly lost almost all vision in her left eye. The pupillary

light reflex was sluggish and hardly elicitable.

No further recurrence of visual impairment was observed in the right eye. VA was 0.15 in

the right eye and light perception in the left. Both optic nerve heads presented a milky-white

appearance (Figure 14A, B). The VFs did not reveal any change in the defects in the right eye

(peripheral constriction and central scotoma), while testing was not performed in the left eye

because of the serious visual loss (Figure 13E, F). The patient underwent repeated orbital and

cranial MRI and laboratory examinations that consistently provided evidence against multiple

sclerosis, acute optic neuritis or vasculitis.

Case 2: A 50-year-old woman had diabetes mellitus for 12 years. Ten years prior to this

study, at the age of 40 years, she noticed progressive visual disturbance in her right eye. The

progression of the central visual loss lasted for only 3 days, but the narrowing of the VF

continued for the following 2 weeks.

The subject’s VA was 0.15 in the right eye and 1.0 in the left. The right optic disk had an

oedematous swelling, whereas the left was normal. No signs of diabetic retinopathy were

observed. The temporal part of the VF in her right eye was constricted to 35º, while the VF in

the left eye remained normal.

Upon neurological examination, the MRI was found to be normal and the laboratory tests

did not indicate any other pathology than diabetes and hypertension. Thiogamma (600 mg/day)

was also administered because diabetic neuropathy was suspected to be the cause of the visual

loss.

32

Figure 13. Progression of kinetic VF loss in the right and left eyes in case 1. (A, B) VFs

after the first attack of NAION. Nasal inferior altitudinal narrowing of the isopters (tested with

W4.5, W4.3 and W4.1 stimuli, respectively) and an enlarged blind spot are to be found in the

VF of the right eye (A), while concentric narrowing of the isopters (W4.3 and W4.1) may be

observed in the VF of the left eye (B). (C, D) Impairment of the VFs after the second attack: In

the right eye (C) the enlarged blind spot has already engulfed half the temporal central area. In

the left eye (D), further shrinkage of the isopters extends to two-thirds of the central visual area

(W4.5, W4.2). (E, F) The VFs after the last attack of NAION. In the right eye (E), the centro-

coecal scotoma covers almost the whole central area. In the left eye (F) VF testing was not

possible because of the lack of fixation.

33

Figure 14. Fundus photographs by

fluorescence angiography of the right (A)

and left (B) eyes in case 1; of the right (C)

and left (D) eyes in case 2, and of the right

eye (E) in case 3. No photograph was taken

of the left eye in case 3 because of the lack

of fixation.

No change in VA or VF occurred during the subsequent year. Two years later, the

patient suddenly lost vision in the left eye. Her ophthalmologist registered VA of 0.15 in the

right eye and 0.08 (finger counting from a distance of 4 meters) in the left. The right optic

disc was pale and the left was oedematous. The possibility of Foster–Kennedy syndrome, as

a consequence of the intracranial pathology, was again excluded. No other symptoms have

appeared since then. Her vision has never recovered: VA remains at 0.15 in the right eye and

0.1 in the left. Both optic nerve heads have become atrophic (Figure 14C, D). No diabetic

retinopathy has developed. Her VF defects have changed during the past 2 years (Figure 15).

No reproducible VEPs could be detected.

Case 3: A 51-year-old woman had non-insulin dependent diabetes mellitus for 12

years. At the age of 42, she noticed a progressive visual deterioration in her left eye, which at

that time was ascribed to cataract formation. In the left eye, the retina was obscured by lens

opacification. The VA was 0.4, which seemingly correlated well with the condition of her

lens. Cataract surgery was performed. However, no improvement of vision was detected

thereafter. Best corrected VA was 0.04. The head of the optic nerve was pale.

Figure 15. Kinetic VF impairments in the right (A) and left (B) eyes in case 2.

Bilateral, relatively altitudinal, concentric VF defects were observed with W4.5 and W4.2

stimuli, respectively.

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The right eye similarly exhibited signs of cataract formation. The appropriate surgery

resulted in a VA of 0.6. Seven months after surgery the subject’s vision in her right eye had

decreased to 0.1. Only a mild optic disc oedema was observed, which turned to optic atrophy

within 2 months (Figure 14). Again, no signs of diabetic retinopathy were found. The VFs

displayed a marked constriction of up to 15–20º in the right eye, while only a paracentral

remnant of the VF could be detected in the left eye (Figure 16). No VEPs could be recorded.

Figure 16. Kinetic VF impairments in the right (A) and left (B) eyes in case 3. There is a marked constriction of the VF in the right eye and a paracentral remnant of the VF in the left eye (W4.5).

Beside NAION no alternative explanation could be found for the subject’s sudden

visual loss. No neurological signs were present and the cranial and orbital MRI excluded

multiplex sclerosis. Chemical blood tests and all immunological tests excluded other

pathologies of visual loss.

4.5. Clinical studies V.: Differential diagnosis of concentric visual field defects

using electrophysiological methods

128 eyes of 72 patients with concentric VF defect were analyzed in our laboratory

between January 1st, 2002 and 31st December, 2005. The patients’ clinical and

electrophysiological data were analyzed retrospectively. Mean age was 47.6 years with a

range of 11–75 years.

The results were compared to control data from 58 healthy, age matched control

subjects with no ophthalmological diseases. The clinical characteristics of the patients are

listed in Table 10.

Ophthalmological examination included assessments of appropriate VA, refraction and

intraocular pressure. Slit-lamp examinations, ophthalmoscopy, and Goldmann perimetry

35

were carried out as well. Electrophysiological examinations (VEP, PERG and ERG) were

recorded according to the standard method described Chapter 3.

The implicit time and the amplitude of the VEP, PERG and ERG waves were analyzed.

Data were analyzed with two-way ANOVA. P < 0.05 was considered significant.

Among the 72 patients 20 RP, 1 choroidal osteoma, 1 MAR, 2 optic nerve

melanocytoma, 11 NAION, 4 dysthyroid ophthalmopathy, 4 toxic neuropathy, 1 diabetic

neuropathy, 9 cerebrovascular circulatory disturbances, 5 optic nerve compression caused by

intracranial tumors and 7 empty sella syndrome were found. The possibility of malingering

had arisen in 3 cases. Although we found electrophysiological alterations in 4 cases, the

aetiology remained unclear.

The characteristic electrophysiological alterations of the diseases are listed in Table 11.

Group Patients (eyes) Gender Age (year) Degree of visual field defect Male Female Range >20º 5–20º <5º

Retinitis pigmentosa 20 (40) 6 14 23,5 12-35 18 13 9Choroidal osteoma 1 (2) 1 53,0 1 1MAR 1 (1) 1 43,0 1Optic disk melanocytoma 2 (2) 2 59,0 58-60 1 NAION 11 (17) 3 8 61,2 36-75 8 7 2Dysthyroid ophthalmopathy4 (8) 1 3 49,7 38-63 4 4 4Toxic neuropathy 4 (8) 2 2 50,0 47-53 4 4Diabetic neuropathy 1 (2) 1 49,0 2Cerebrovascular disease 9 (18) 2 7 55,8 41-74 5 8 5Compressive optic 5 (10) 5 48,3 40-57 2 4 4 neuropathy Empty sella syndrome 7 (14) 1 6 44,7 22-72 8 4 2Functional 3 (6) 1 2 39,5 32-47 2 4Unknown aetiology 4 (8) 2 2 35,2 7-72 4 4 MAR: melanoma associated retinopathy syndrome; NAION: nonarteritic ischaemic optic neuropathy

Table 10. Clinical data of the 72 patients

RP comes first into our mind among the numerous ophthalmological diseases in the

case of concentric VF defect. The decrease of retinal function was detected by the

extinguished scotopic and maximal ERG. We found residual responses only in four cases,

that time the implicit time of the OP was delayed and its amplitude was decreased.

Examining the VEPs, we found both normal, and altered answers with pathological wave

form, delayed implicit time and decreased amplitude.

The choroidal osteoma of the papillomacular bundle caused choroidal atrophy in the

right eye. Both the latencies of the VEP and PERG were markedly delayed, and the

amplitude of the VEP was diminished. We did not find any choroidal atrophy in the left eye;

however, a concentric VF defect developed in this side, too. The implicit time of the VEP

was slightly delayed and the amplitude slightly decreased.

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During the 13-years observation period of the melanocytoma in the right eye of our

patient the VA decreased, and her VF narrowed. The implicit time and amplitude alterations

of the VEP deteriorated, and the implicit time of OP delayed, too.

PVEP PERG Maximal ERG OPL A L A A L A

Retinitis pigmentosa ■: → →■: N

↓↓↓↓

■: → → ↓↓ ↓↓ N ↓↓

Melanoma associated retinopathy syndrome

■: N■: N

N ■: N N negative N N

Choroidal osteoma ■: → →■: → →

↓↓↓↓

■: → → N N N N

Optic disk melanocytoma ■: N■: N

↓↓↓↓

■: N N N → N

Nonarteritic ischaemic optic neuropathy

■: → →■: N

↓↓↓↓

■: N ↓ N N ↓

Toxic neuropathy ■: N■: N

↓↓↓

■: N N N N N

Diabetic neuropathy ■: → →■: → →

N ■: → → N → → → N

Dysthyroid ophthalmopathy ■: N■: N

N ■: N N N N N

Compressive optic neuropathy ■: → ■: N

↓↓↓

■: N N ↓ N ↓↓

Cerebrovascular diseases ■: N■: N

↓↓

■: N ↓ N →→ ↓

Empty sella syndrome ■: N■: N

↓↓↓↓

■: N N N N N

Functional ■: N■: N

N ■: N N N N N

(VEP: pattern visual evoked potential, PERG: pattern electroretinogram, ERG: electroretinogram, OP: oscillatory potencial, L: latency, A: amplitude, ↓/→: p<0,05, ↓↓ / →→: p<0,01)

Table 11. Characteristic electrophysiological alterations in diseases with concentric VF

defect.

Decreased VEP amplitude was found in toxic neuropathy.

Our diabetic patient’s neuropathy was detected by the VEP, and her maculopathy was

diagnosed by the delayed latency of the PERG and the OP.

We did not found any pathological alterations among patients with endocrine

orbitopathy.

5. Discussion

General depression or peripheral contraction of the VF can occur in several disorders

along the visual pathways; however, psychogenic and technical factors should also be taken

into consideration.

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Concentric VF defect can be caused by diseases of the retina, the optic nerve, the optic

tract and the visual cortex. The pathomechanism of the VF constriction differs in these

diseases. The electrophysiological examinations can help the diagnosis in questionable cases.

Causes of concentric VF defects are listed in Table 12 (below).

Causes of concentric visual field defects82

1. Praeretinal factors1.1. Pupillary factors 1.2. Media opacities (contact lenses, corneal oedema, scars, cataracts, vitreous

haemorrhage)2. Primary chorioretinal / Photoreceptor dystrophies

2.1. Chorioideremia, Gyrate atrophy2.2. Myopic degeneration2.3. Retinitis pigmentosa2.4. Cancer- and autoimmunity-associated retinopathies (carcinoma associated retinopathy [CAR], melanoma associated retinopathy [MAR]) 2.5. Diabetic retinopathy2.6. Occlusion of central retinal vein

3. Ganglion-cell/ axon- and optic nerve lesions3.1. Glaucoma3.2. Ischemic optic neuropathy (NAION)3.3. Toxic-nutritional-metabolic neuropathy3.4. Compressive neuropathy3.5. Severe pre-eclampsia3.6. Increased intracranial pressure causing optic neuropathy

4. Bilateral occipital infarct (with macular spare of the centrum) 5. Functional visual field loss

5.1. Neurasthenia 5.2. Hysteria5.3. Malingering

6. Technical factors6.1. Inappropriate contrast of stimulus-target/background ratio6.2. Inappropriate correction 6.3. Too rapid target movement 6.4. Slow response times

Table 12. Causes of concentric VF defects

Primary chorioretinal / Photoreceptor dystrophies

Chorioideremia is caused by the XL-R inherited mutations in the chorioideremia gene

resulting in a diffuse atrophy of the RPE and the choriocapillaris. ,, The first symptom

manifesting in males in early childhood is usually impaired night vision followed by a

progressive narrowing of the field of vision (tunnel vision), and later a decrease in the VA.

The ophthalmologic features are characteristic; however, the field constriction and the

progression of the VA resemble the RP.

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The ERG, VEP and mfERG alterations reveal the exact severity of the disease. Gyrate atrophy is a rare, AR disorder resulting from the deficiency of the mitochondrial matrix enzyme ornithine-aminotransferase, the gene of which is located on chromosome 10q26. The exact mechanism of chorioretinal degeneration remains unknown.

Clinically, gyrate atrophy patients initially develop myopia and reduced night vision, usually before the end of the first decade of life.,, Ophthalmoscopy reveals the presence of numerous sharply demarcated circular areas in the peripheral retina which gradually increase in number and size, coalesce, and spread from the peripheral to the central fundus, forming lesions with a "gyrate" or garland-like border. Reduced peripheral vision with constriction of the VFs is obvious in the 2nd decade. Complete loss of vision is associated with involvement of the macula.

ERG abnormalities are already present at an early stage of the disease, with impaired rod and cone responses, progressing to an extinguished response.,,

In high myopia the VF constriction depends on the severity of peripheral degeneration and the ERG turn to be subnormal. However, we can differentiate between this peripheral retinal degeneration and the true degenerative myopia, which is a retinal dystrophy accompanied with myopia. In this case the ERG is extinguished.

The term of retinitis pigmentosa (RP) refers to a heterogeneous group of inherited photoreceptor dystrophies characterized by AD, AR and XL-R inheritance patterns, in which the rods and cones undergo progressive degeneration. Over 100 genes can cause RP. The large number of RP genes identified can be grouped into the following functional classes: (1) proteins of the visual cascade, (2) proteins of the visual cycle, (3) photoreceptor cell transcription factors, (4) proteins related to catabolic processes, and (5) genes of unknown function. The ‘final common pathway’ remains photoreceptor cell death by apoptosis. The outer segments progressively shorten, followed by loss of the rod photoreceptor. This occurs mostly in the mid-periphery of the retina, or, in some cases, the inferior retina, thereby suggesting a role for light exposure.

Affected patients report impaired dark adaptation, night blindness and peripheral vision loss. Although initially there may be only a peripheral ring scotoma, typically from 30° to 50°, with time this scotomatous area breaks out of the periphery and infringes on the central field, until only a small area of vision remains, sometimes associated with a temporal island.

ERG may be severely subnormal or undetectable as soon as in the early stage of the disease. For the follow- up of the progression of the photoreceptor loss, PERG, VEP and mfERG seemed to be appropriate.

The PVEPs are elicited predominantly from the central 10º of the VF, which is well preserved for a long period during the progression of RP. This is why we offer the VEP tests

39

for evaluation of the progression of the disease. Three types of VEP waveforms were found: normal VEPs, VEPs with bifid pattern and VEPs with broad waveform. These alterations might be reflecting different patterns of the cone receptor loss in the central retina. It may depend on the type of inheritance, the time of the examination, etc. The interpretation of these VEP alterations needs further investigation.

PERGs were severally depressed in all of our patients. Following the photoreceptor loss, transneural degeneration of the ganglion cells can be expected. However, histological examination did not find significant difference in the number of ganglion cells in RP patients with serious or mild visual loss., This result suggests that the visual impairment in RP is determined not only by the extent of degeneration, but also by the localisation of the degenerated patches within the foveal area. This concept is in agreement with our mfERG observations, which revealed involved and intact areas in the central retina.

According to our observations, mfERG can show the involved and intact retinal areas in the central 30º of the VF. The different preserved areas in the two eyes may be complemented in the visual cortex (filling-in phenomenon), which can help visual processing. VEP and PERG alterations in RP are important in the follow-up of the progression.

Further investigations into transneural degeneration are very important for any prospective therapeutic intervention.

In cancer- and autoimmune-associated retinopathies autoantibodies directed at various retinal protein antigens cause progressive vision loss. An underlying malignancy places this condition in the category of paraneoplastic syndromes. When no malignancy is found, patients are considered to have autoimmune retinopathy. Recoverin, , alfa-enolase and photoreceptor cell-specific nuclear receptor gene product initiate a cascade of events, leading to increased phosphorylation of rhodopsin, which activates apoptotic pathways, resulting in diffuse photoreceptor degeneration with or without inflammation. Ganglion cells and retinal vasculature are spared.

Patients with MAR have IgG autoantibodies that react with human rod bipolar cells antigens.

The clinical features of paraneoplastic retinopathy and autoimmune retinopathy are generally similar. In cases of CAR, vision loss can occur before malignancy is diagnosed. ,, ,, In contrast, MAR usually develops years after removal of a malignant melanoma of the skin, often at the stage of skin malignant melanoma metastatic spread.

Symptoms and signs depend on which retinal elements are affected. CAR affects both rods and cones. Patients with CAR usually have prominent involvement of central vision, resulting in markedly decreased VA, loss of colour vision, and central scotomas. Later total blindness develops. In contrast, patients with MAR, when antibodies against bipolar cells

40

interfere with rod function, often have near-normal VA, colour vision and central VFs. Peripheral or mid-peripheral field loss can usually be demonstrated. Generally, there is no ophthalmologic sign of the disease. Later on, attenuation of the arterioles with thinning and mottling of the RPE may develop.

The ERG alteration (extinguished in CAR syndrome, negative type ERG in MAR syndrome) can draw the attention to the origin of the sometimes unusual symptoms.

Optic neuropathy has been suggested as a specific complication of diabetes, but its nature and pathogenesis are still unclear. Proposed pathophysiological mechanisms include toxic effects of prolonged hyperglycaemia, increased susceptibility of the optic nerves to inflammation in diabetes, a disturbance of schwann cell metabolism, and anterior ischemic optic neuropathy (or vascular pseudopapillitis).,, Beyond optic neuropathy, peripheral neovascularisation can also result in VF narrowing.

Ganglion-cell, axon- and optic nerve lesions

The diagnosis in glaucoma is based on the ‘typical’ VF defects caused by pressure

differences between the intraocular fluid and CSF (rather than the absolute value of the IOP).

This difference results in a passive neuronal intracellular fluid flux in the axons of the

ganglion cells close to the lamina cribrosa. The location and the thickness of the axons within

the optic nerve at the level of the lamina cribrosa determine their sensitivity and

susceptibility to damage. Intracellular fluid flow locally depletes adenosine triphosphate,

disrupting active axonal transport, leading to cell death in turn.

The papillomacular bundle of optic nerve axons, - which, as part of the parvocellular pathway, serve central vision - remain intact for long. PERG is the only objective method for the detection of the ganglion cell damage. During progression more and more axons and ganglion cells will be damaged, resulting in peripheral narrowing of the VF. Glaucoma will cause magnocellular pathway damage.

Nonarteritic anterior ischemic optic neuropathy (NAION) is one of the most frequent causes of sudden visual loss in middle-aged or elderly patients. ,,,, Its annual incidence has been estimated to be 10.3 per 100,000 individuals aged 50 years or older. It was be presumed that an infarction of a blood vessel supplying the intrascleral portion of the optic nerve is the cause of the sudden visual loss. The infarction may occur by defective autoregulation, while others have emphasized the importance of an anatomical variation of the optic disk (‘disk at risk’) as an important predisposing factor.,, The acute hypoxia of the optic nerve head results in axoplasmic flow stasis in the optic nerve fibers, swallowing the axons in the level of the cribriform plate of the disk. The fall of perfusion pressure in the optic disc capillaries due to nocturnal arterial hypotension and elevation of IOP results in marked ischemia and that precipitates visual loss, which is usually discovered when waking up in the morning.

41

The type and severity of the axon loss can be evaluated by VF examination, provided that the visual acuity is good enough for fixation. In the acute stage it can be an arcuate defect, but later all the four quadrants of the VF can be constricted resulting in an indefinite concentric defect.

Electrophysiological examination shows the severity of the axon damage and in young patients – when the manifestation of this disease is rare –, thus helping differential diagnosis.

Arteritic ischemic optic neuropathy (AION) is a sight-threatening autoimmune disease caused by giant cell vasculitis of the medium arteries. We stress the importance of differentiation between AION and NAION because of their different treatment and prognosis. Blindness can occur by central retinal artery occlusion or ischaemic optic neuropathy.

Toxic-nutrition-metabolic neuropathy can be caused by exogenous or endogenous factors. If the subchiasmatic part of the optic nerve is the site of the damage, bilateral central scotomas or a narrowing of the peripheral visual field will develop. VEPs are subnormal in these cases, while ERGs are normal.

There are drugs (thioridasine and indometacinum) which cause RPE lesion followed by depigmentation and atrophy of the retina. ERGs are subnormal or extinguished in such cases.

Vigabatrin can cause retinal cone dysfunction. An idiosyncratic drug reaction within the neurosensory retina may underlie the pathogenesis of the VF loss with interindividual susceptibility. Vigabatrin causes irreversible inhibition of GABA aminotransferase with consequent elevation of GABA., Sildenafil (Viagra), vardenafil and tadalafil are selective inhibitors of cyclic guanosine monophosphate specific phosphodiesterase 5. Phosphodiesterase 6 isoenzyme is found predominantly in retinal photoreceptors and is very important in the phototransduction cascade.

Tobacco, alcohol, chloramphenicol and ethambutol cause ganglion cell loss. The pathogenesis of tobacco–alcohol amblyopia remains elusive; combined mechanisms of toxic insults from tobacco compounds and/or ethyl alcohol might be at play, concurrent with nutritional deficiencies.,Tobacco-derived compounds including reactive oxygen species and cyanide reduce mitochondrial respiratory activity, damage mitochondrial DNA, and induce alterations of mitochondrial morphology.

Chloramphenicol is well known to inhibit mitochondrial protein synthesis, causing retinal ganglion cell and nerve fiber loss, with demyelinisation of the optic nerve, involving predominantly the papillomacular bundle.

Ethambutol might interact with Cu-containing cytochrome oxydase c (complex IV) and Fe-containing NADH:Q oxidoreductase (complex I), thus damaging the mitochondrial respiratory chain, inducing axonal swelling in the optic chiasm and in the intracranial portion of the optic nerve.

42

Tetracycline, minocycline, lithium, Accutane, nalidixic acid, and corticosteroids (both use and withdrawal) can cause benign intracranial hypertension and papilledema.

In compressive optic neuropathy, beside the direct compression that the tumor exerts on the optic nerve, a general intracranial pressure elevation has to be taken into account. Peripheral axons will suffer the direct effect of compression and disturbances of the axoplasmic and blood flow.

Infiltrative neuropathy - sarcoidosis, tuberculosis, cryptococcus infection, leukaemia, lymphoma, and metastatic cancer) can also result in VF narrowing.

The disc swelling in papilloedema is the result of axoplasmic flow stasis with intra-axonal oedema in the area of the optic disc. The subarachnoid space of the brain is continuous with the optic nerve sheath. Thus, as the CSF pressure increases, the pressure is transmitted to the optic nerve, and the optic nerve sheath acts as a tourniquet to impede axoplasmic transport. This leads to a buildup of material at the level of the lamina cribrosa, resulting in the characteristic swelling of the nerve head.

Bilateral occipital infarct (with macular spare of the centrum)

The posterior cerebral artery supplies the visual cortex. There are many causes of the

bilateral posterior cerebral artery occlusion: multiple emboli from a mural thrombus of the

vertebral or basilar artery, etc. The visual cortex has a secondary blood supply from the

carotid system. In infarction of both occipital lobes, the accessory blood supply from the

carotid system may preserve the macular projection. A person with bilateral occipital infarct

with macular sparing will present with a preserved central acuity but only a small field,

usually 2 to 3°, which means functional blindness.

Functional field defects

Patients with functional VF loss can be placed into one of three general groups:

neurasthenics, hysterics, or malingerers. The neurasthenic patient usually has many

complaints, not limited to the visual system, or to the field loss. The degree of field or visual

defect varies from one examination to another, sometimes during the examination as well.

The patient with hysteria has a single ocular complaint. The malingerer may be the most

difficult patient with functional loss, particularly if he has previously been examined by

another physician, and has acquired more experience with field testing than he had when first

examined.

Severely contracted VFs can also be seen in exacting patients who want to be sure they see the object and, therefore, unduly contract the fields.

The PVEP is useful to determine the organic origin of the visual loss.

43

6. Summary

Several diseases causing lesions along the visual pathways can result in concentric VF defect. In the discussion we collected these diseases and analysed the possible pathological processes that may result in VF defects. The aim of our investigation was to find the appropriate electrophysiological method or combination of methods for objective evaluation of the functional loss in these disorders.

For this purpose the first step was to introduce the modern, standard electrophysiological methods into the clinical practice in Hungary.

1. We determined the normal parameters of standard ERG, mfERG, PERG and PVEP and published our first experiences.

2. We drew attention to the importance of combined use of electrophysiological methods, especially in the neuroophthalmological practice.

3. We observed three types of mfERG alterations in RP. Further we found better preserved focal areas within the central visual field. The mfERG results were against the continuous degeneration of the photoreceptors towards the fovea. These where better preserved areas in the central retina, which may help the analysis of the visual information in the visual cortex in patients with RP.

4. Although ERG examinations have priority in the diagnosis of RP, we point to the importance of PERG and PVEP tests in the determination of the progression of the disease. The three types of VEP alterations may reflect not only the severity of the functional loss in the foveal area but may indicate histological different photoreceptor damage, too.

5. We were the first to publish a monocular case of MAR syndrome. 6. Our investigation in NAION patients was important not only in the evaluation of the

severity of visual deficits, but also provided further help to solve differential diagnostic problems in young patients with acute visual loss with papilloedema.

7. Conclusions

The electrophysiological investigations are not widely used in the ophthalmological

practice, although they are the methods to objective evaluation of the functional loss along

the visual pathway.

Different disorders resulted in concentric VF loss. The combined use of this methods

help to find the origin of the field loss, help to differential diagnosis in the cases when

clinical symptoms, the visual loss and the ophthalmoscopic alterations are not in agreement.

This new methods may give new information on the pathophysiology of the disorders

of visual pathway.

44

8. Acknowledgements

I am indebted to Prof. Dr. Márta Janáky, Prof. Dr. György Benedek and Prof. Dr. Lajos Kolozsvári who provided me a chance to participate in this research. I also thank Kati Mayer and Gabriella Dósai-Molnár for their valuable technical assistance.

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